Insights from FOURIER: Obesity-associated cardiovascular risk

December 2025

Treatment with evolocumab reduced cardiovascular risk in obese individuals with atherosclerotic cardiovascular disease.

Kang YM, Giugliano RP, Keech AC, et al. Obesity-associated cardiovascular risk and benefit from PCSK9 inhibition. A prespecified analysis from FOURIER. J Am Coll Cardiol 2025; doi.org/10.1016/j.jacc.2025.10.036.

 

STUDY SUMMARY

Objective

To investigate the efficacy of evolocumab by baseline body mass index (BMI) in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial.

 

  
Study design

The FOURIER trial was a randomized, double-blind, placebo-controlled study that included 27,564 patients (40 to 85 years of age) with stable atherosclerotic cardiovascular disease (ASCVD) (1). This report describes a prespecified analysis of this trial.

 

  
Study population

Eligible patients were required to have low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL or non–high-density lipoprotein cholesterol levels ≥100 mg/dL on a background of optimized lipid-lowering therapy. In total, 27,500 patients with baseline BMI information were included in the analysis; 11,546 (42%) were overweight (BMI ≥25-<30 kg/m2) and 10,942 (40%) were obese (BMI ≥30 kg/m2).

 

  
Main study variables

The primary endpoint was a 4-point composite of major adverse cardiovascular events (MACE), i.e. cardiovascular death, myocardial infarction (MI), stroke, hospitalization due to unstable angina, or coronary revascularization. The key secondary endpoint was the 3-point composite MACE of cardiovascular death, MI, or stroke.

 

  
Methods

Patients were categorized by BMI subgroup as no obesity (BMI <30 kg/m2, n = 16,558), class 1 obesity (BMI 30 to <35 kg/m2, n = 7,496), and class 2 or 3 obesity (BMI ≥35 kg/m2, n = 3,446).  Efficacy analyses were performed on the intention-to-treat population using a stratified Cox proportional hazards model. The association between BMI and cardiovascular risk was investigated in the placebo arm at 3 years, adjusted for baseline clinical characteristics. The primary and key secondary endpoints were compared between the evolocumab and placebo groups stratified by BMI considered as both a continuous variable (modelled per 5-unit increase in BMI above 30 kg/m2) and categorical variable (<30, 30 to <35, ≥35 kg/m2). An exploratory analysis evaluated the association between randomized treatment arm, BMI and high-sensitivity C-reactive protein (hs-CRP, categorized as <3 vs ≥3 mg/L).

 
Key results

In the placebo group, higher BMI was associated with an increased risk of MACE, with an 11% higher risk of the primary endpoint and a 16% higher risk of the secondary endpoint per 5-unit-higher baseline BMI above 30 kg/m2.

 

Evolocumab had similar LDL-C lowering efficacy irrespective of BMI. At 48 weeks, the placebo-adjusted least square mean reduction in LDL-C with evolocumab treatment was 60.8% among patients with BMI <30 kg/m2 versus 56.3% in those with BMI ≥30 kg/m2.

 

Treatment with evolocumab was associated with 11% and 14% relative risk reduction in the primary endpoint in patients with BMI <30 kg/m2 and 30-34.9 kg/m2, respectively, but 29% relative risk reduction for patients in the highest BMI category. A similar pattern for reduction in relative risk with evolocumab was observed for the secondary endpoint (18% and 16% for patients in the two lower BMI categories versus 33% for patients in the highest BMI category) (Table 1). For both endpoints, the absolute risk reduction tended to be greater with higher baseline BMI (Table 1). The number needed to treat (NNT) to prevent one primary endpoint over 3 years was 18 for patients in the highest BMI category.

 

Table 1. Risk of primary and secondary outcomes per BMI category

 

BMI <30 kg/m2

(N=16,558)

BMI 30-34.9 kg/m2

(N=7,496)

BMI ≥35 kg/m2

(N=3,446)
Primary endpoint; %*      
Placebo 13.4 15.7 18.2
Evolocumab 11.9 13.9 12.6
HR (95% CI) 0.89 (0.81-0.98) 0.86 (0.75-0.98) 0.71 (0.59-0.86)
ARR; % 1.4 1.8 5.7
       
Secondary endpoint; %*      
Placebo 9.2 10.2 12.6
Evolocumab 7.2 9.1 8.5
HR (95% CI) 0.82 (0.72-0.92) 0.84 (0.71-1.00) 0.67 (0.53-0.86)
ARR; % 2.0 1.1 4.1

* Kaplan-Meier incidence at 3 years

ARR absolute risk reduction; CI confidence interval; HR Hazard ratio

 

In an exploratory analysis, patients with both BMI ≥30 kg/m2 and baseline hsCRP >3 mg/L derived a 25% relative reduction in the risk of the primary endpoint with evolocumab treatment; this compared with 14% relative risk reduction when either obesity or elevated hsCRP was present.
Author conclusions Individuals with obesity and ASCVD face an elevated risk of MACE compared with those without obesity, and evolocumab helps to attenuate this risk.

Comment

 

This prespecified analysis of FOURIER provides several key findings. First, as shown by data from the placebo group, patients with obesity are at elevated risk of cardiovascular events. The incidence of the primary endpoint was 18.2% among patients with BMI ≥35 kg/m2 versus 13.4% in those with BMI <30 kg/m2 (Table 1). Furthermore, in a continuous modelled analysis, the risk of the primary endpoint increased by 11% per 5-unit-higher baseline BMI above 30 kg/m2. Second, the study showed that while evolocumab was similarly effective in lowering LDL-C levels irrespective of BMI, the clinical benefit of treatment was enhanced in patients in the highest BMI category (≥35 kg/m2), who were at highest risk. With evolocumab, the incidence of the primary endpoint was lower than in the placebo group with BMI <30 kg/m2 (12.6% versus 13.4%, respectively). Third, the results of an exploratory analysis indicate that the reduction in cardiovascular risk appeared to be accentuated in obese patients with concomitant high inflammatory risk.

 

These findings are notable when considering the unmet clinical needs in patients with obesity. Cardiovascular disease is the leading cause of death in obese individuals, responsible for two-thirds of all deaths (2).  With escalating obesity prevalence, more than doubling cardiovascular deaths due to high BMI worldwide since 1990 (3), there is an urgent need for therapeutic approaches to address this challenge.

 

Obesity results in cardiometabolic dysregulation through a range of interrelated mechanisms including insulin resistance, endothelial dysfunction, systemic inflammation, dyslipidemia, and neurohormonal activation, which accentuate cardiovascular risk (2,4). Emerging evidence also links higher PCSK9 levels with obesity, reinforcing the interplay between metabolic dysfunction and lipid regulation (5,6).

 

Evidence to suggest greater reduction in cardiovascular risk with concomitant obesity and high inflammatory risk (versus those with either characteristic) is currently hypothesis generating given the nature of exploratory analyses. Whether the combination of BMI and hsCRP may identify those patients at higher residual cardiovascular risk who derive greater benefit from intensive lipid lowering therapy is a key question that warrants further study.

 

References

  1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
  2. Obesity and cardiovascular disease: an ESC clinical consensus statement Euron Heart J 2024; doi.org/10.1093/eurheartj/ehae508.
  3. Lopez-Jimenez F, Di Cesare M, Powis J, et al. The weight of cardiovascular diseases: Addressing the global cardiovascular crisis associated with obesity. Global Heart 2025; doi.org/10.5334/gh.1451.
  4. Lopez-Jimenez F, Almahmeed W, Bays H, et al. Obesity and cardiovascular disease: Mechanistic insights and management strategies. A joint position paper by the World Heart Federation and World Obesity Federation. European Journal of Preventive Cardiology 2022;29(17):2218–37.
  5. Ruscica M, Ferri N, Macchi C, et al. Liver fat accumulation is associated with circulating PCSK9. Ann Med 2016; 48: 384-91.
  6. Levenson AE, Shah AS, Khoury PR, et al. Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women. Pediatr Diabetes 2017;18:755–60.

Key words:  FOURIER; obesity; cardiovascular risk; evolocumab